Thiazole compounds



Patented Oct. 25, 1938 UNITED sures 2,134,015 7 amazon: COMPOUNDS RobertR. Williams, Roselle, N. 1., as lignor Research Corporation, New York,N. Y., a corporation of New Yor No Drawing. AppllcationDecember 23, 103,Serial Nix 117,418

3Claims.

This invention relates to the production 01' thiazole compounds, moreparticularly those which are useful in the synthesis 01' compoundsrelated to the antlneuritic vita-min, generally 5 known as vitamin B1. I

Vitamin B1 and related compounds having similar physiological propertiesare useful in the treatment of diseases, notably beriberi, and aid inthe maintenance and well being, and in the 10 growth of animalsincluding man. A number of research workers have been endeavoring to produce synthetic compounds which areidentical with or closely related tothe natural antineuritic vitamin and which have physiological propllerties comparable to those of this vitamin. Among the compounds whichhave proven to be useful in syntheses 01' this nature are the thiazolederivative designated 4-methyl-5-p-hydroxyethyl-thiazole and saltsthereof.

80 The object of the present invention is to provide thiazole compoundssuitable for the synthetic production of compounds related to theantineuritic vitamin.

In accordance with the invention, a salt of vitamin B1 is caused toreact with a water solution of a soluble sulphite and the resultingthiazole derivative is separated from the reaction mixture and purified.

A specific method by which thiazole compounds embodying the inventionmay be produced is as follows:

One gram of vitamin B1 chloride hydrochloride and 2 grams of sodiumsulphite are disssolved in 15 cc. of water, sulphurous acid is addedtill the pH is about 5 and the solution is allowed to stand at roomtemperature for 48 hours. It is then filtered from any material, chiefly2-methy1-6- amino pyrimidine 5 methyl sulphonic acid, which hascrystallized out.

The filtrate is made slightly alkaline with an alkali hydroxide, such assodium hydroxide, and extracted repeatedly with chloroform. Ether or asimilar solvent may be used in place of chloroi'orm if desired. Thechloroform extract is dried over sodium carbonate and evaporated todryness leaving an oily residue of faint basic odor 1 analyzing for thecomposition CsHaNSO. This substance consists oi. the tree thiazolederivative 50 base, 4-methyl-5-p-hydroxy ethyl-thiazole, in asubstantially pure state. This has Y the structural formula =c-cmomorr=c-cmomon in which X represents an anion, for example, an acid radical,such as H804, or an elementary anion, such as the chloride ion. By wayof example, thesubstance may be converted into its hydrochloride bydissolving it in dilute hydrochloric acid and evaporating the solutionto dryness. The resulting hydrochloride may be purifled by dissolving ina minimum amount'of absolute alcohol and adding dioxane which causes,the hydrochloride to separate upon standing for several hours in theform of colorless crystals.

An aqueous solution of the hydrochloride on treatment with a solution ofplcrolonic acid in methanol precipitates a crystalline picrolonate whichmelts with decomposition at 184 C. When an ether solution of picric acidis added to an ether solution of the free base a crystalline picrate isobtained which melts at 162-163 C.

The vitamin B1 chloride hydrochloride employed in the above describedmethod is deproduced by the foregoing scribed in an article by R. R.Williams-set 11., Journal or American Chemical Society, vol. 56, p.11870934) and'vol. 5'7 p. 517 (1935). Instead of the chloridehydrochloride of vitamin 31 other salts thereof, such as thecorresponding bromine neuritic properties. For-example, this thiasbie.

or a salt thereof, such as the hydrobromide, may

be caused to react with the compound 2-methyl- 6-amino-5-bromomethylpyrimidine,"or a salt thereof, such as the hydrobromide, to produce thebromide hydrobromide of vitamin B1.v A synthesis of the-above nature isrevealed in the article entitled Synthesis of vitamin B1" which 1publishedin conjunction with Dr. .1. K. cune I in the Journal of theAmerican Chemical Society. 58, 1504 (1936). p 1

What is claimed is:

d1. 'lhiasolecompoimdsdthemlpconsistina in which x represents an anion.h

2. The thiasole derivative havina the formula:

OHs' d-c-cmcmon M V c.

3.r'l'hiasole salts having the formula:

inwhichXisananion,

nom'r R. wnmm.

